ABSTRACT The etiology of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson?s disease (PD) is heterogeneous, and epidemiological and laboratory studies suggest exposures to environmental toxins as a putative risk factor triggering the processes ultimately resulting in a neurodegenerative disease. Protein misfolding and aggregation are key common pathological features of these diseases. The accumulation of ?- synuclein (?Syn) aggregates is the hallmark of PD, while abnormal hyperphosphorylation of tau and the accumulation of tau aggregates in the neuronal fibrillary tangles are classically the most dominant etiologic features of AD?s pathology. Chronic exposure to high concentrations of manganese (Mn) results in adverse neurological health effects commonly referred to as manganism, an extrapyramidal disorder characterized by motor disturbances and neuropsychiatric and cognitive disabilities similar to Parkinsonism. While investigating the effects of Mn on ?Syn misfolding and cell-to-cell transfer, pursuant to the objective of our original parent grant award, we unexpectedly discovered that Mn promotes hyperphosphorylation of tau at pathological sites in brain regions associated with Mn-induced motor and cognitive deficits. Interestingly, the phosphorylated tau colocalized with PKC?, suggesting that PKC? kinase may hyperphosphorylate tau. Even though direct ?Syn- tau interactions have been suggested to be neurodegenerative, the precise role of environmental Mn exposure in the development of tau pathology and propagation and subsequent cognitive deficits is still not understood. Thus, this supplemental proposal addressing AD and its related dementias (ADRD) will further characterize the cellular and molecular mechanisms of Mn-induced tau pathology and exosomal transmission and its role in cognitive deficits. Our proposal will test the novel hypothesis that Mn exposure promotes the PKC?-dependent hyperphosphorylation of the microtubule-associated tau protein and that Mn also promotes the propagation of tau pathology between cells via exosomes, contributing to cognitive impairment and the neurodegenerative processes underlying environmentally linked AD and ADRD. Specific objectives of the proposal are i) to determine tau hyperphosphorylation and exosomal release in cell and animal models of Mn neurotoxicity and to characterize the role of PKC? and ?Syn during this Mn insult, and ii) to confirm the presence of Mn (plus other metals) and hyperphosphorylated tau in human brain and CSF samples and to validate exosomal tau release in those samples. Our proposed studies will offer novel insights into the role of environmental metal exposure in the propagation of misfolded tau pathology and its relevance to the etiology of AD and ADRD- associated cognitive deficits.